NO174465B - Analogous Procedure for Preparing Therapeutic 1-Acyl-2,3-Dihydro-4- (1H) -quinolinone-4-oxime Derivatives - Google Patents

Description

The present invention relates to an analogous method for the preparation of a therapeutically active l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivative represented by the general formula (I):

wherein R<1> represents a straight-chain or branched alkyl group containing 1 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a lower alkyloxy group, a methoxymethyl group , a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from a group consisting of a straight-chain alkyl group or branched and contains 1 to 4 carbon atoms, a hydroxy group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<4 >represents a carboxymethyl group, a sulfo group, a methanesulfonyl group or a methoxyphosphoryl group, R<5> and R<6> are equal ller different and represent hydrogen atoms, halogen atoms, hydroxy groups, methylthio groups, methylsulfinyl groups, methanesulfonyl groups, N,N-dimethyl-

amino groups, nitro groups, acetyl groups, methyl groups, trifluoromethyl groups, methoxycarbonyl groups or methoxy groups and the bond shown with a wavy line represents a bond of anti-form or syn-form, and pharmaceutically acceptable salts thereof with organic and inorganic bases as well as solvates of said derivatives and solvates of said salts. The compounds can be used for the treatment and/or prevention of hypertension, edema and/or to remove ascites.

For the treatment of hypertension, benzothiazide derivatives or so-called "loop" diuretics have been used to a large extent to lower blood pressure. These agents act mainly on the distal part of the renal tubule or loop of Henle and increase the renal excretion of electrolytes and water. However, it is known that many of these diuretics exhibit several negative reactions, e.g. hypokalemia, hyperuricemia, lowering of sugar tolerance and disturbances in lipid metabolism.

Diuretics have also been used in the treatment of edema resulting from retention of water and electrolytes based on cardiac and renal insufficiency or on metabolic disturbances, but such conventionally used diuretics show only little effectiveness against the retention of ascites, which is often observed in patients with abdominal tumor or liver cirrhosis.

These benzothiazide diuretics and "loop" diuretics are known to have common chemical structures.

On the basis of the foregoing, it has been desirable to develop new diuretics which are useful in the treatment of hypertension, edema and to remove ascites and which do not cause the aforementioned negative reactions, by producing compounds whose chemical structure is new and differs from the known diuretics.

One purpose of the present invention is to produce new 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives and salts thereof, solvates of said derivatives and solvates of said salts.

A further purpose of the present invention is to produce intermediate compounds, namely new 1-acyl-2,3-dihydro-4(1H)-quinolinone derivatives for the production of 1-acyl-2,3-dihydro-4(1H)-quinolinone The -4-oxime derivs. These intermediates are represented by the general formula

(III):

wherein R<1> represents a straight-chain or branched alkyl group containing 3 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 2 to 4 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from a group consisting of an alkyl group which is straight chain or branched and contains 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<5 >represents a hydrogen atom, a halogen atom, a hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N-dimethylamino group , nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and R<6> represents a

halogen atom, a hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group.

The present invention is based on the preparation of l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives, namely O-sulphate, O-mesylate, O-methylphosphate and O-carboxymethyl, ether, especially O-sulphate of 4-oxime.

The compounds produced according to the present invention which contain these substituents have a strong hypotensive, anti-edematous and diuretic effect, as well as activity to remove ascites and are very useful in the treatment of diseases and disorders as mentioned above.

As a result of extensive research regarding the development of new dihydro-quinolinone-oxime derivatives which have a satisfactory diuretic effect, the inventors of the present invention have found that l-acyl-2,3-dihydro-4(1H)-quinolinone-4 -oxime derivatives, especially l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulphate exhibit a strong diuretic activity which can be used in the treatment and/or prevention of hypertension, edema and/ or to remove ascites, which consequently satisfies these requirements and has produced the present invention.

The compounds of formula I can be prepared by

a) to react a l-acyl-2,3-dihydro-4(1H)-quinolinone derivative represented by the general formula (II)

wherein R<1> represents a straight-chain or branched alkyl group containing 1 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a lower alkyloxy group, a methoxymethyl group , a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from a group consisting of a straight-chain alkyl group or branched and contains 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<5> and R<6> are the same or different and represent hydrogen atoms, halogen atoms, hydroxyl groups, methylthio groups, met ylsulfinyl groups, methanesulfonyl groups, N,N-dimethylamino groups, nitro groups, acetyl groups, methyl groups, trifluoromethyl groups, methoxycarbonyl groups or methoxy groups, with hydroxylamine in organic solvents to form a corresponding 1-acyl-2,3-dihydro-4(1H)-quinolinone-4 -oxime derivative represented by formula (I<1>)

where R<1>, R<2>, R<3>, R<5> and R<6> as well as the bond shown with a wavy line have the same meanings as defined for formula (I),

and then reacting said derivative with a complex of

sulfur trioxide, halogenated phosphoric acid esters, halogenated acetic acids, halogenated acetic acid esters or with methanesulfonyl halides and, if necessary and desirable, to hydrolyze the product thus formed, or

b) when R<4> in the general formula (I) means a sulfo group, to react a 1-acyl-2,3-dihydro-4(1H)-quinolinone derivative

represented by the general formula (II)

wherein R<1>, R<2>, R3, R5 and R<6> have the same meaning as defined above, with hydroxylamine-O-sulfonic acid in the presence of an organic base, such as pyridine, N,N-dimethylaniline or potassium acetate , or an inorganic base, such as potassium carbonate or sodium carbonate.

For example, the known 2,3-dihydro-4(1H)-quinolinone and its derivatives, such as 5-chloro-2,3-dihydro-4(1H)-quinolinone and 7-chloro-2,3-dihydro-4 (1H)-quinolinone (French Patent 1,514,280), 6-chloro-2,3-dihydropjr4 (1H)-quinolinone (The Journal of the American Chemical Society, volume 71, pages 1901-1904 (1949) and U.S. Patent 2,558 211) and 8-chloro-2,3-dihydro-4(1H)-quinolinone (French Patent 1,514,280) or new mono- or di-substituted 2,3-dihydro-4(1H)-quinolinones, generally by reacting known mono- or di-substituted anilines with T-butyrolactone or with acrylic acid and subjecting the resulting N-carboxyethylated aniline with mono- or di-substitution(s) to cyclocondensation by Friedel-kraft reaction (described in step 1 of Example 8 ; the products thereof are listed in Table 8), such as 6-chloro-7-fluoro-2,3-dihydro-4(1H)-quinolinone, 7-chloro-6-fluoro-2,3-dihydro-4(1H) -quinolinone and 6,7-difluoro-2,3-dihydro-4(1H)-quinolinone, are reacted with reactive derivatives of carboxylic acids to introduce acyl groups n, preferably acid halides, in organic solvents and if necessary and desirable in the presence of an acid binding agent to obtain 1-acyl-2,3-dihydro-4(1H)-quinolinone derivatives as intermediate compounds.

Chloroform, dichloromethane, ether, tetrahydrofuran, dioxane, benzene or ethyl acetate can be used as an organic solvent; organic bases such as pyridine, triethylamine or N,N-dimethylaniline or inorganic bases such as potassium carbonate, sodium carbonate or sodium bicarbonate can be used as the acid-binding agent. As acid halide, acid halides corresponding to R<1> in the general formula I can be used, such as 2-methylbenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2-bromobenzoyl chloride, 4-chlorobenzoyl chloride, 2,2- dimethylpropionyl chloride or propionyl bromide.

The intermediate compounds thus obtained, l-acyl-2,3-dihydro-4(1H)-quinolinone derivatives, are reacted with hydroxylamine in organic solvents such as methanol, ethanol, tetrahydrofuran or dimethylformamide to prepare the corresponding l-acyl-2,3- dihydro-4(1H)-quinolinone-4-oximes which are then reacted with sulfonating agents such as sulfur trioxide pyridine complex or sulfur trioxide dimethylformamide complex, or with halogenated phosphoric acid esters such as methyl dichlorophosphate in the presence of bases such as n-butyllithium, sodium hydride or phenyllithium or with halogenated acetic acid or its ester such as bromoacetic acid or methyl bromoacetate in the presence of bases such as potassium hydroxide or sodium hydroxide or with methanesulfonyl halides such as methanesulfonyl chloride in the presence of bases such as triethylamine or diethylaniline followed, if necessary and desired, by hydrolysis by conventional methods to obtain the corresponding products, namely l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-suldonic acid-de rivates, monomethyl ester derivatives of l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-0-phosphate, l-acyl-2,3-dihydro-4(1H)-quinolinone-4- oxime-O-acetic acid derivatives and 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-methanesulfonyl derivatives.

The above-mentioned intermediate compounds 1-acyl-2,3-dihydro-4(1H)-quinolinone derivatives can also be reacted with hydroxylamine-O-sulfonic acid in organic solvents such as methanol, ethanol, tetrahydrofuran or dimethylformamide in the presence of pyridine, N,N-dimethylaniline , potassium acetate, sodium carbonate or potassium carbonate to obtain 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-0-sulfonic acid derivatives.

To show the applicability of the compounds according to the invention, data on diuretic, antihypertensive and antiedematous activity as well as the activity to remove ascites for representative compounds are listed below. In the case of R<4>, the free acid form is listed in the table above, but these compounds can also be isolated as salts of corresponding acids.

Experimental example 1

Diuretic activity in dogs

Mixed-breed dogs weighing 7 to 15 kilograms were fasted overnight. The animals were kept supine under pentobarbital anesthesia (30 mg/kg body weight, i.v.) and physiological salt solution was continuously infused into the femoral vein via catheter at a rate of 0.15 ml/kg/min. The animals were then laparotomized and the left urethra was cannulated to collect the urine for 10 minute periods. Compounds to be tested were administered intravenously and changes in the amount of urine were recorded. Percentage increase in urine output was calculated using the formula listed below: Increase in urine output = (Urine output in the 90 minute period after administration of the compound)

- [(Urine amount in the 30-minute period before administration) x 3]

Percentage increase in = (increase in urine volume at test pre-urine volume bond) (increase in urine volume at

furosemide) x 100.

The results are shown below:

All the compounds tested showed considerable uretic activity.

Experimental example 2

Suppressive effect on carraqeenin-induced paw edema in rats

Compound to be tested or phenylbutazone was administered orally to groups of Wistar rats (weighing about 120 grams), each group consisting of 3 to 5 animals. 1 hour after administration, 0.1 ml physiological saline containing 1% carrageenan was injected subcutaneously into the left hind paw. The volume of each paw was measured before and 3 hours after the injection of carrageenan and the change in volume was divided by the volume before the injection to calculate the edema index. The dose at which edema was suppressed by 30%, ED30 was calculated for each compound.

The results are shown below.

All the tested compounds showed a considerable anti-edematous effect.

Experimental example 3

Hypotensive effect in spontaneously hypertensive rats

The compound to be tested was administered orally once daily for 7 consecutive days to groups of spontaneously hypertensive male rats (SHR weighing 250 to 300 g), each group consisting of 3 to 5 animals. Mean blood pressure of SHR ranged from 170 to 190 mmHg. Blood pressure was measured before and after administration with a plethysmograph.

The results are shown below.

Considerable hypotensive activity was observed for all the compounds tested.

Experimental example 4

Removal of ascites from tumor-bearing mice

2 days after intraperitoneal transplantation of 10 cells/animal of P388 murine leukemia cells into 6- to 7-week-old BDF^ mice, compounds to be tested were administered intravenously to groups of the tumor-bearing mice, each group consisting of 6 animals . 5 hours after administration, the volume of ascites was measured. The ratio of removal was calculated for each compound on the relative_volume of ascites. The results are listed below.

All the compounds tested showed considerable activity, stronger than furosemide in removing ascites in tumor-bearing mice.

Experimental example 5

Acute toxicity

Compounds to be tested were administered intraperitoneally to groups of ICR mice weighing approx. 20 grams. Each group consisted of 5 animals. 7 days after administration, mortality was determined.

The results are shown below.

The doses in the experiment described above are considerably higher than what is necessary for the pharmacological activity of the compounds. Therefore, it is of the opinion that these connections have large safety margins.

As shown by the experimental examples described above, these compounds according to the present invention exhibit a strong diuretic activity which can be utilized in the treatment and/or prevention of hypertension, edema and/or to remove ascites and also have a large margin of safety within the dose ranges showing these pharmacological activities. Therefore, these compounds are of great use in the treatment of edema caused by functional insufficiency of heart, kidney or liver, hypertension and accumulation of cancerous ascites. The 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives according to the present invention represented by the general formula I can form pharmaceutically acceptable salts with organic or inorganic bases. Typical examples of such salts of the compounds represented by the general formula I include pharmacologically acceptable salts such as alkali metal salts, such as sodium salts, potassium salts, etc.; alkaline earth metal salts, such as calcium salts, etc.; salts of organic bases, such as ammonium salts, benzylamine salts, diethylamine salts, etc.; salts of amino acids, such as arginine salts, lysine salts, etc. The 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives produced by the present invention can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical mixtures containing the 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives together with corresponding pharmaceutically acceptable carriers. The pharmaceutical mixtures may be in solid form, e.g. tablets, granules, powder and capsules or in liquid form, e.g. as aqueous solutions for injection or suspensions for injection prepared with suspending excipients such as Tween 80 or gum arabic. The mixtures can be administered orally or intravenously, but can also be administered subcutaneously, intradermally or intramuscularly. Furthermore, the mixture can be formulated for administration by inhalation, e.g. as aerosol for topical application as ointment or as suppositories. While the dose varies depending on the age and condition of the patient, the condition and nature of the disease, etc., a daily dose for an adult of approx. 1 to 5000 mg, preferably from approx. 10 to 1000 mg.

In what follows, the present invention shall be described with reference to the examples below, but shall not be considered to be limited to these.

Example 1

Preparation of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone

To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone (20.0 g)/pyridine (26 g) and dichloromethane (200 ml) was added dropwise 2-methylbenzoyl chloride (26 g ) at room temperature with stirring. The mixture was stirred at reflux for 4 hours. The reaction mixture was poured into 500 mL of water, then shaken with additional dichloromethane (1000 mL). The organic layer was washed once with 1 N HCl (100 mL), twice with water (200 mL each) and once with saturated NaCl solution and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and then the residue was recrystallized to obtain 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone (yield 28 g) as white crystals.

Melting point 106.5-108.1<*>C ;IR (KBr, cm"<1>): 1695, 1655, 1405, 1380, ;NMR (CDC13, ppm): 2.34 (3H, s), 2 .80 (2H, t), 4.16 (2H, t), ;7.00 - 8.00 (7H, m, aromatic). ;Example 2 ;Preparation of 6-chloro-1-(2,4- dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone. ;To a mixture of 6-chloro-2,3-dihydro-4(1H)-quinolinone ;(20 g), pyridine (26 g) and dioxane (200 ml) 2,4-dichlorobenzoyl chloride (30 g) was added dropwise while cooling at 0°C to 5°C and with stirring. The mixture was allowed to react at room temperature for a further 3 hours. The reaction mixture was poured into 500 ml of water and then shaken with dichloromethane (1000 mL).The organic layer was washed once with 1N HCl (100 mL), twice with water (200 mL each) and then once with saturated aqueous sodium chloride solution (200 mL) and dried over anhydrous sodium sulfate.Dichloromethane was removed in vacuo and the residue was recrystallized with dichloromethane and n-hexane to obtain 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone (yield 35 g) as wh ite crystals. ;Melting point: 176.8 - 177.8°C ;IR (KBr, cm"<1>): 1700, 1670, 1480, 1390 ;NMR (CDC13, ppm): 2.87 (2H, t), 4, 22 (2H, t), ;7.07 - 8.04 (6H, m, aromatic). ;Example 3 ;Preparation of 8-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4 (1H)-quinolinone. ;To a mixture of 8-chloro-2,3-dihydro-4(1H)-quinolinone ;(30 g), pyridine (52 g) and dioxane (400 ml) was added dropwise 2, 4-dichlorobenzoyl chloride (100 g) at room temperature; with stirring. The mixture was then heated to reflux for 5 hours. After cooling, the reaction mixture was subjected to the procedure described in Example 2 and 61 g of 8-chloro-1-(2,4 -dichlorobenzoyl)-4-[(2,4-dichlorobenzoyl)oxy]-1,2-dihydroquinoline was obtained. All product was then dissolved in ethanol (400 mL) and 4.5 g of NaOH was slowly added to the solution over a 30 minute period under stirring, and while maintaining a temperature of 0° C. to 5° C. Stirring was then continued at room temperature for 1 hour. The reaction mixture was poured into 1000 ml of water, where after shaking with 200 ml of dichloromethane. The organic layer was washed twice with water (300 mL each time) and then once with saturated aqueous NaCl solution (300 mL) and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was recrystallized with dichloromethane and n-hexane to give 8-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone (yield 32 g) as white crystals. ;Melting point: 157.0 - 159.4°C ;IR (KBr, cm"<1>): 1700, 1680, 1440, 1280 ;NMR (CDC13, ppm): 2.73 (2H, t), 3, 97 (2H, t), ;6.73 - 7.84 (6H, m). ;Example 4 ;Preparation of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-3-methyl -4(1H)-quinolinone To a cooled (-20°C to -15°C) solution of diisopropylamine (4.7 g) in anhydrous tetrahydrofuran (100 ml) was added dropwise a n-hexane- solution (29 ml) of 1.6 N butyllithium over a 30 minute period under a nitrogen atmosphere and stirring was continued for 30 minutes after the mixed solution was returned to 0° C. Then the solution was cooled to -75° C with acetone-dry ice and 15 g of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone were dissolved in 150 ml of anhydrous tetrahydrofuran and added dropwise over the course of 1 hour. stirred for an additional 1 h at -75°C and methyl iodide (18 g) was added with stirring over 30 min.The reaction mixture was then slowly warmed to 0°C over 2 h and made s ur under cooling with 2 N hydrochloric acid until it was slightly acidic. The reaction mixture was poured onto 300 ml of water, then shaken with ethyl acetate (500 ml). The organic layer was washed once with saturated aqueous NaCl solution (200 mL) and dried over anhydrous sodium sulfate. Methyl acetate was removed in vacuo and the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate- mixture (4:1) to obtain 6-chloro-1-(2,4-dichloro-benzoyl)-2,3-dihydro-3-methyl-4(1H)-quinolinone (yield 7.8 g) as white crystals. ;Melting point: 156.7 - 159.4'C ;IR (KBr, cm"<1>): 1690, 1650, 1470, 1385 ;NMR (CDCl3, ppm): 1.35 (3H, d), 3, 61 (1H,m), ;4.38 (2H,d), 6.89 - 7.95 (6H,m) ;Example 5 ;Preparation of 7-chloro-1-(2,4-dichlorobenzoyl)-2 ,3-dihydro-4(1H)-quinolinone ;To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone ;(25 g), pyridine (32 g) and dioxane (200 ml) 2,4-dichlorobenzoyl chloride (37 g) was added dropwise while cooling at 0°C to 5°C with stirring. The mixture was allowed to react at room temperature for a further 3 hours. The reaction mixture was subjected to the procedure described in Example 2, and 43 g of 7-Chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone was obtained as white crystals.;M.P.: 159.0 - 162.9°C;IR (KBr, cm "<1>): 1695, 1660, 1395, 1195 ; NMR (CDCl 3 , ppm): 2.78 (2H, t), 4.08 (2H, t), ; 7.03 - 7.95 (6H, m, aromatic) ;Example 6 ;Preparation of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-sulfonic acid potassium salt (compound 6) ;For a mixture of 7-chloro-2,3-dihydro-1-( 2-methylbenzoyl)-4(1H)-quinolinone (10.0 g) obtained in example 1, methanol (150 ml) and dichloromethane (100 ml) were added at room temperature to hydroxyamine-O-sulfonic acid (11 g) under constant stirring. The mixture was stirred at room temperature for 30 minutes and an aqueous solution of potassium carbonate (14 g in 20 ml of water) was added at once. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography using a chloromethane-methanol mixture (5 : 1) and recrystallized with a mixed solvent of methanol carbon tetrachloride to obtain 7-chloro-2,3-dihydro-1-( 2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt (yield: 12.0 g) as white crystals. Melting point: 189.0°C (decomposition) ;IR (KBr, cm"<1>): 1660, 1380, 1240 ;NMR (DMSO-d6): 2.22 (3H, s), 2.81 (2H, t), ;3.73 (2H, t), 6.90 - 7.95 ;(7H, m, aromatic) ;Example 7 ;Preparation of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl )-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt (compound 6). ;Step 1 ;To a mixture of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4( 1H)-quinolinone (14.9 g) obtained in Example 1, and ethanol (250 ml) was added to hydroxylamine hydrochloride (7 g) and pyridine (8.5 g) and the mixture was refluxed for 1.5 hours After cooling, the reaction mixture was poured into 1000 ml of water and the precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H )-quinolinone-4-oxime (yield: 13.6 g) as white crystals. ;M.P.: 166.0 - 168.4°C ;IR (KBr, cm"<1>): 3330, 1635, 1400 ;NMR (DMS0-d6): 2.20 (3H, s), 2.81 (2H, t), ;3.77 (2H, t), 7.05 - 7.98 ;(7H, m, aromatic) ; Step 2; The product from tr inn 1 (13.6 g) was dissolved in chloromethane (250 ml) and sulfur trioxide pyridine complex (7 g) was added. The reaction mixture was stirred at room temperature for 24 hours and approx. 150 ml of the solvent was removed in vacuo. To the residue was added methanol (200 ml) and then aqueous potassium carbonate solution (6 g in 10 ml of water) was added all at once, and the mixture was subjected to the procedure described in Example 6, and 13 g of 7-chloro-2,3- dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt was obtained as white crystals, IR and NMR spectrum as well as melting point were exactly the same according to the procedure of the product in Example 6 Example 8 Preparation of 7-chloro-6-fluoro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt (compound 18) Step 1: Preparation of 7-chloro-6-fluoro-2,3-dihydro-4(1H)-quinolinone. ;A mixture of polyphosphoric acid (600 g) and 3-(3-chloro-4-fluoro-phenylamino)propionic acid (38 g) which was prepared from 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate by the procedure of W.S. Johnson et al. (The Journal of American Chemical Society, Volume 71, Page 1901, (1949)) was stirred at 110°C for 70 minutes. The reaction mixture was poured into 1500 ml of water and then shaken with dichloromethane (1500 ml). The organic layer was washed twice with saturated aqueous NaCl solution (200 ml each time) and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was subjected to silica gel column chromatography using a mixed solvent (n-hexane : ether = 4 : 1) to obtain 7-chloro-6-fluoro-2,3-dihydro- 4(1H)-quinolinone (yield 20 g) as pale yellow crystals. ;Melting point: 192.0 - 194.0°C ;IR (KBr, cm""1) : 3350, 1645, 1250, 1160 ;NMR "(DMSO-d6+CDCl3,ppm) : 2.61 (2H, t ) , 3.52 (2H, t) , ;6.83 (1H, d), 7.43 (1H,d) ;(Step 2) ;Preparation of 7-chloro-6-fluoro-1-(2- methylbenzoyl)-2,3-dihydro-4(1H)-quinolinone. ;The product from step 1 (15 g), 2-methylbenzoyl chloride (17 g), pyridine (12 g) and dichloromethane (200 ml), was subjected to reaction - and the purification procedure described in Example 1 and 7-chloro-6-fluoro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone (21 g) was obtained.;Melting point: 84, 9 - 88.7°C ;IR (KBr, cm"<1>): 1700, 1665, 1480, 1370 ;NMR (CDC13, ppm): 2.38 (3H, s), 2.81 (2H, t ), ;4.16 (2H, t), 7.16 - 7.78 (6H, m) ;(Step 3) ;Preparation of 1-(2-methylbenzoyl)-7-chloro-6-fluoro-2, 3-Dihydro-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt. ;The product from step 2 (10 g), hydroxylamine-O-sulfonic acid (3.6 g), potassium carbonate (4.4 g) and methanol (100 ml) was subjected to the reaction and purification procedure described in Example 6, and 1-(2-Methylbenzoyl)-7-chloro-6-fluoro-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid potassium salt (4 g) was obtained as white crystals. ;Melting point: 204.1°C (decomposition) ;IR (KBr, cm"<1>): 1650, 1375, 1210 ;NMR (DMSO-d6,ppm): 2.23 (3H, s), 2.82 (2H, t), ;3.75 (2H, t), 7.16 - 7.79 (6H, m, aromatic) ;Example 9 ;Preparation of 7-chloro-1-(2,4-dichlorobenzoyl)- 2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid potassium salt (compound 11) ;To a mixture of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro -4(1H)-quinolinone (14.5 g) obtained in Example 5, methanol (200 ml) and dichloromethane (200 ml) 4.6 g of hydroxylamine-O-sulfonic acid were added with stirring at room temperature. for 30 minutes at room temperature, an aqueous solution of potassium carbonate (5.6 g in 10 ml of water) was added at once and stirring was continued for 2 hours. The precipitated crystals were removed by filtration and the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography using dichloromethane-methanol mixture (10 : 1) and recrystallized with methanol and carbon tetrachloride to obtain 7-chloro-1-(2,4-dichlorobenzoy) 1)-2,3-dihydro-4(1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt (yield 10.0 g) as white crystals. ;Melting point: 217.5°C (decomposition) ;IR (KBr, cm"<1>): 1660, 1395, 1240 ;NMR (DMS0-d6,ppm): 2.80 (2H, t), 3.59 (2H, t), ;7.12 - 7.93 (6H, m, aromatic) ;Example 10 ;Preparation of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H )-quinolinone-4-oxime-0-sulfonic acid sodium salt (compound 11). ;To a mixture of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone (14 .5 g) obtained in Example 5, methanol (200 ml) and dichloromethane (200 ml) was added to 4.6 g of hydroxylamine-0-sulfonic acid with stirring at room temperature. After stirring for 30 minutes at room temperature, an aqueous solution of sodium carbonate (4.3 g in 10 ml._water) all at once and stirring was continued for 2 hours. The precipitated crystals were removed by filtration and the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography using dichloromethane- methanol mixture (10 : 1) and recrystallized with methanol and carbon tetrachloride to obtain 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1 H)-quinolinone-4-oxime-O-sulfonic acid sodium salt (yield 8.0 g) as white crystals. ;Melting point: 176.5°C (decomposition) ;IR (KBr, cm"<1>): 1670, 1395, 1235 ;NMR (DMSO-d6,ppm): 3.05 (2H, t), 3.90 (2H, t), ;7.25 - 8.15 (6H, m, aromatic). ;Example 11 ;Preparation of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4( 1H)-quinolinone-4-oxime-0-sulfonic acid potassium salt (compound 11) ;(Step 1) ;To a mixture of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H )-quinolinone (17.5 g), obtained in Example 5, and ethanol (250 ml) were added hydroxylamine hydrochloride (7 g) and pyridine (8.5 g) and the mixture was heated under reflux for 1, 5 hours. After cooling, the reaction mixture was poured into 1000 ml of water and the precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro -4(1H)-quinolinone-4-oxime (yield 16 g) as white crystals.;M.P.: 230.7 - 232.3"C;IR (KBr, cm"<1>): 3250, 1635, 1420, 945 ;NMR (DMS0-d6,ppm): 2.72 (2H, t), 3.57 (2H, t), ;7.05 - 7.94 (6H, m, aromatic) ;(Step 2) ; P the crude product from step 1 (16 g) was dissolved in dichloromethane (250 ml) and sulfur trioxide pyridine complex (7 g) was added. The reaction mixture was stirred at room temperature for 24 hours and the solvent was removed in vacuo. To the residue was added methanol (200 ml) and then an aqueous potassium carbonate solution (6 g in 10 ml of water) at once, and the mixture was subjected to the same procedure as described in Example 9. 13 g of 7-chloro-1-( 2,4-Dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid potassium salt was precipitated as white crystals. IR and NMR spectrum as well as melting point were completely according to the product in example 9. ;Example 12 ;Preparation of 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime -O-acetic acid (compound 14). ;To a mixture of bromoacetic acid (7.7 g), potassium hydroxide (6.5 g) and water (60 ml) was slowly added 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4( 1H)-quinolinone-4-oxime (12.7 g) while cooling in an ice bath. The mixture was stirred for 24 hours at room temperature, then acidified with 2N HCl to pH 3.0 in an ice bath. The acidic mixture was poured into 150 ml of water and then shaken with ethyl acetate (500 ml). The organic layer was washed once with saturated aqueous NaCl solution (500 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was subjected to silica gel column chromatography using dichloromethane-methanol mixture (9:1) to give 6-chloro-2,3-dihydro-1-(1-oxopropyl)- 4(1H)-quinolinone-4-oxime-O-acetic acid (yield 10.5 g) as white crystals. ;Melting point: 142.8 - 144.0°C ;IR (KBr, cm"<1>): 3300 - 2800, 1740, 1650, 1480, 1390. ;NMR (DMS0-d6,ppm): 1.03 ( 3H, t), 2.52 (2H, q), 2.84 (2H, t) ;3.79 (2H, t) 4.69 (2H, s), ;7.26 - 7.75 (3H , m, aromatic) ;Example 13 ;Preparation of 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime-0-phosphoric acid monomethyl ester (compound 15) ; To a cold (-75°C) solution of 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime (7.5 g) in anhydrous tetrahydrofuran (150 ml) an n-hexane solution (21 ml) of 1.6 N butyllithium was added dropwise over a 30-minute period under a nitrogen atmosphere, and stirring was continued for 30 minutes at -75° C. To the mixture was added dropwise methyl dichlorophosphate ( 4.9 g) over a 30-minute period at -75°C and stirring continued for an additional 30 minutes at -70°C to -60°C for 2 hours. The reaction mixture was slowly warmed to 0°C and then acidified with 1N HCl until the pH became 2.0. The acidic mixture was stirred for 5 hours at room temperature, poured onto 200 ml of water and shaken with ethyl acetate (500 ml). The organic layer was washed once with saturated aqueous NaCl solution (200 mL) and dried over anhydrous sodium sulfate. Ethyl acetate was removed in vacuo and the residue was subjected to silica gel column chromatography using a dichloromethane-methanol mixture (19:1) to give 6-chloro-2,3-dihydro-1-(1-oxopropyl) -4(1H)-quinolinone-4-oxime-O-phosphoric acid monomethyl ester (yield 7.2 g) as white crystals. ;Melting point: 71.9 - 75.0°C ;IR (KBr, cm"<1>): 3420, 2950, 1680, 1395, 1195 ;NMR (DMS0-d6,ppm): 1.01 (3H, t ), 2.50 (2H, q), 2.88 (2H, t) ;3.62 (2H, d) 3.78 (2H, t), ;7.22 - 7.85 (3H, m, aromatic) ;Example 14 ;Preparation of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime mesylate. ;For a mixture of 6-chloro-1 -(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime (10.0 g), triethylamine (4.1 g) and dichloromethane (150 ml) were added dropwise to meansulfonyl- chloride (3.5 g) at -20°C with stirring. The mixture was stirred at -20°C for 30 minutes and dichloromethane (300 mL) was added. The reaction mixture was respectively washed with 1N HCl, saturated aqueous sodium bicarbonate solution and then with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was recrystallized with ether and n-hexane to give 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime mesylate ( yield 11 g) as white crystals. ;Melting point: 197.4 - 198.1'C ;IR (KBr, cm"<1>): 1660, 1365, 1180 ;NMR (DMSO-d6,ppm): 3.03 (2H, t), 3, 38 (3H, s), 3.72 (2H, t); 7.12 - 7.92 (6H, in, aromatic).; The compounds from Examples 15 to 266 are collected in the following Tables 8 to 18 together with corresponding IR and NMR data (NMR data were generally measured at 90 MHz, except for some data measured at 60 MHz and marked with asterisks (*)) and melting or splitting points.

The methods by which these compounds are prepared can be classified into three groups as shown below.

Typical examples of formulations of the compounds of formula I will now be described below.

Formulation A (capsules)

40 g of compound 6, 645 g of lactose and 15 g of magnesium stearate were weighed and mixed until the mixture was homogeneous. The mixture was then filled into No. 1 hard-gelatin capsules of 350 mg each to form the capsule preparation.

Formulation B (tablets)

50 g of compound 6, 800 g of lactose, 120 g of potato starch, 15 g of polyvinyl alcohol and 15 g of magnesium stearate were weighed. The weighed amount of compound 6, lactose and __ potato starch were mixed until the mixture was homogeneous. Then an aqueous solution of polyvinyl alcohol was added to the mixture and granulated by wet process. The granules were then dried, mixed with magnesium stearate and pressed

tablets each weighing 200 mg.

Formularin<g> C (powder)

100 g of compound 11, 890 g of lactose and 10 mg of magnesium stearate were weighed and mixed until the mixture was homogeneous to obtain a 10% powder preparation.

Formulation D (rectal suppository)

100 g of compound 4, 180 g of polyethylene glycol 1500, 720 g of polyethylene glycol 4000 were ground in a mortar and formulated into suppositories by melting and casting in a suitable form.

Formulation E fine injection)

1 g of compound 11 was weighed and dissolved in 200 ml of distilled water for injection. The solution was filtered and sterilized. Two milliliters each of the sterilized solution were poured into 5 ml ampoules and sealed to obtain preparation for injection.

Claims (7)

1. Analogous method for the preparation of a therapeutically active l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivative represented by the general formula (I): wherein R<1> represents a straight-chain or branched alkyl group containing 1 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a lower alkyloxy group, a methoxymethyl group , a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from a group consisting of a straight-chain alkyl group or branched and contains 1 to 4 carbon atoms, a hydroxy group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<4 >represents a carboxymethyl group, a sulfo group, a methanesulfonyl group or a methoxyphosphoryl group, R<5> and R<6> are equal are different and represent hydrogen atoms, halogen atoms, hydroxy groups, methylthio groups, methylsulfinyl groups, methanesulfonyl groups, N,N-dimethylamino groups, nitro groups, acetyl groups, methyl groups, trifluoromethyl groups, methoxycarbonyl groups or methoxy groups and the bond shown with a wavy line represents a bond of anti -form or syn-form, and pharmaceutically acceptable salts thereof with organic and inorganic bases as well as solvates of said derivatives and solvates of said salts characterized by) to react a l-acyl-2,3-dihydro-4(1H)-quinolinone derivative represented by the general formula (II) wherein R<1> represents a straight-chain or branched alkyl group containing 1 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a lower alkyloxy group, a methoxymethyl group , a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from eji group consisting of an alkyl group which is straight chain or branched and contains 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<5> and R<6> are the same or different and represent hydrogen atoms, halogen atoms, hydroxyl groups, methylthio groups, me ethylsulfinyl groups, methanesulfonyl groups, N,N-dimethylamino groups, nitro groups, acetyl groups, methyl groups, trifluoromethyl groups, methoxycarbonyl groups or methoxy groups, with hydroxylamine in organic solvents to form a corresponding 1-acyl-2,3-dihydro-4(1H)-quinolinone-4 -oxime derivative represented by formula (I<1>) where R<1>, R<2>, R<3>, R<5> and R<6> as well as the bond shown with a wavy line have the same meanings as defined for formula (I), and then to react said derivative with a complex of sulfur trioxide, halogenated phosphoric acid esters, halogenated acetic acids, halogenated acetic acid esters or with methanesulfonyl halides and, if necessary and desirable, to hydrolyze the thus formed product, or b) when R<4> in the general formula (I) means a sulfo group, to react a 1-acyl-2,3-dihydro-4(1H)-quinolinone derivative represented by the general formula (II) wherein R<1>, R<2>, R3, R5 and R<6> have the same meaning as defined above, with hydroxylamine-O-sulfonic acid in the presence of an organic base, such as pyridine, N,N-dimethylaniline or potassium acetate , or an inorganic base, such as potassium carbonate or sodium carbonate. 2. Process according to claim 1 in the preparation of a 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivative, and at least one of R<5> or R<6> represents a halogen atom in 7-position, characterized by using correspondingly substituted starting compounds. 3. Process according to claim 2 in the preparation of a 1-acyl-2,3-dihydro-4(1H)-quinolone-4-oxime derivative where R<1 >represents phenyl, 2-halophenyl, 2-methylphenyl, 2- ethyl-phenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-nitrophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2,6-difluorophenyl, 2,3-dimethoxyphenyl, 4-chloro-2- methylphenyl, 1,1-dimethylethyl or 2-chloro-1,1-dimethylethyl, characterized by using correspondingly substituted starting compounds. 4. Process according to claims 2 and 3 in the preparation of a l-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivative where the bond shown with a wavy line in formula I represents a bond of sight-form. characterized by using correspondingly substituted starting compounds. 5. Intermediate compound in the synthesis of a 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivative characterized in that the intermediate compound is a 1-acyl-2,3-dihydro-4 (1H)-quinolinone derivative represented by the general formula (III): wherein R<1> represents a straight-chain or branched alkyl group containing 3 to 8 carbon atoms, a straight-chain or branched halogenated alkyl group containing 2 to 4 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a methoxymethyl group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a phenyl group substituted with 1 to 5 substituents which are the same or different and selected from a group consisting of an alkyl group which is straight or branched and contains 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkyloxy group, a trifluoromethyl group and a halogen atom, R<2> and R<3> are the same or different and represent hydrogen atoms or methyl groups, R<5 >represents a hydrogen atom, a halogen atom, a hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and R<6> represents a halogen atom, a hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group. 6. Intermediate compound according to claim 5, characterized in that at least one of R<5> or R<6> represents a halogen atom in the 7-position. 7. Intermediate compound according to claim 6, characterized in that R<1> represents a phenyl-, a 2-halophenyl-, a 2-methylphenyl-, a 2-ethyl-phenyl-, a 2-trifluoromethylphenyl-, a 2- methoxyphenyl, a 2-nitrophenyl-, a 4-chlorophenyl-, a 2,4-dichlorophenyl-, a 2,4-dimethylphenyl-, a 2,6-difluorophenyl-, a 2,3-dimethoxyphenyl-, a 4-chloro -2-methylphenyl-, a 1,1-dimethylethyl- or a 2-chloro-1,1-dimethylethyl group.